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Identification of a Fused-Ring 2 '-Deoxyadenosine Adduct Formed in Human Cells Incubated with 1-Chloro-3-buten-2-one, a Potential Reactive Metabolite of 1,3-Butadiene

文献类型： 外文期刊

作者： Zeng, Fang-Mao 1 ; Liu, Lin-Yan 1 ; Zheng, Jin 1 ; Kong, Cong 2 ; An, Jing 1 ; Yu, Ying-Xin 1 ; Zhang, Xin-Yu 1 ; Elfarra 1 ;

作者机构： 1.Shanghai Univ, Sch Environm & Chem Engn, Inst Environm Pollut & Hlth, Shanghai 200444, Peoples R China

2.Chinese Acad Fishery Sci, East China Sea Fisheries Res Inst, Shanghai 200090, Peoples R China

3.Univ Wisconsin, Dept Comparat Biosci, 2015 Linden Dr, Madison, WI 53706 USA

4.Univ Wisconsin, Mol & Environm Toxicol Ctr, Madison, WI 53706 USA

期刊名称：CHEMICAL RESEARCH IN TOXICOLOGY （ 影响因子：3.739； 五年影响因子：4.142 ）

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收录情况： SCI

摘要： 1-Chloro-3-buten-2-one (CBO) is an in vitro metabolite of 1,3-butadiene (BD), a carcinogenic air pollutant. CBO exhibited potent cytotoxicity and genotoxicity that have been attributed in part to its reactivity toward DNA. Previously, we have characterized the CBO adducts with 2'-deoxycytidine and 2'-deoxyguanosine. In the present study, we report on the reaction of CBO with 2'-deoxyadenosine (dA) under in vitro physiological conditions (pH 7.4, 37 degrees C). We used the synthesized standards and their decomposition and acid-hydrolysis products to characterize the CBO DNA adducts formed in human cells. The fused-ring dA adducts (dA-1 and dA-2) were readily synthesized and were structurally characterized as 1,N-6-(1-hydroxy-l-hydroxymethylpropan-1,3-diyl)-2'-deoxyadenosine and 1,N-6-(1-hydroxy-1-chloromethylpropan-1,3-diyl)-2'-deoxyadenosine, respectively. dA-1 exhibited a half-life of 16.0 +/- 0.7 h and decomposed to dA at pH 7.4 and 37 degrees C. At similar conditions, dA-2 decomposed to dA-1 and dA, and had a half-life of 0.9 +/- 0.1 h. These results provide strong evidence for dA-1 being a degradation product of dA-2. dA-1 is formed by replacement of the chlorine atom of dA-2 by a hydroxyl group. The slow decomposition of dA-1 to dA, along with the detection of hydroxymethyl vinyl ketone (HMVK) as another degradation product, suggested equilibrium between dA-1 and a ring-opened carbonyl-containing intermediate that undergoes a retro-Michael reaction to yield dA and HMVK. Acid hydrolysis of dA-1 and dA-2 yielded the corresponding deribosylated products A-1D and A-2D, respectively. In the acid-hydrolyzed reaction mixture of CBO with calf thymus DNA, both A-1D and A-2D could be detected; however, the amount of A-2D was significantly larger than that of A-1D. Interestingly, only A-2D could be detected by LC-MS analysis of acid hydrolyzed DNA from cells incubated with CBO, suggesting that dA-2 was stable in DNA and thus may play an important role in the genotoxicity and carcinogenicity of BD. In addition, A-2D could be developed as a biomarker of CBO formation in human cells.

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